Abstract The ability to regulate emotions is a critical aspect of our adaptive functioning. Caused by abnormal emotional regulation, neuropsychiatric symptoms (NPSs)--agitation, aggression, apathy, depression, etc., are the primary component of the ?non-cognitive? symptoms of Alzheimer?s Disease (AD), which bring colossal caregiving burden and significantly reduce the quality of AD patients. So far, there is no safe and effective pharmacological nor non-pharmacological management for these emotional problems. Prescribed psychiatric drugs currently available may not work in AD because of its unique brain pathology and the unclear underlying mechanism. Substantial clinical studies suggested that the amygdala (AMY) and the prefrontal cortex (PFC) might be two pivotal sites mediating NPSs in AD. However, the circuitry and cellular abnormalities involved have yet to be determined, which are vital knowledge for developing therapeutic strategies for AD?s NPSs. In the meantime, ?sundowning,? a feature of AD describing an increase in agitated behavior in the evening, indicates that sleep disruption is closely related to poor emotion processing in AD. Our overall hypothesis is that the abnormal hypo- or hyper-activity of specific AMY or PFC neurons resulting from AD pathology directly or indirectly, causes NPSs in AD. Increasing sleep can antagonize these abnormalities, thus alleviate NPSs of AD. To test it, we propose to probe the activity dynamic from individual GABAergic or glutamatergic neurons in freely moving AD mice with deep-brain calcium imaging tools. Genetically engineered AD mice models (VGAT- Cre/APP/PS1 and VGLUT2-Cre/APP/PS1) are ready in our facility for targeting these neurons. Apathy (nest construction, grooming, and exposure to opposite-sex conspecifics), aggression (resident-intruder paradigm), and depression (tail suspension) behavior will be tested to manifest NPSs. Furthermore, we will examine the effect of sleep potentiation on NPSs severity and neuronal activities. Neuronal hyperactivity is becoming an emerging biomarker of AD cognitive deficit. Sleep is becoming a promising intervention to reduce AD neuropathology. Our first goal is to identify the functional biomarker of NPSs of AD. Our second goal is to determine if increasing sleep could improve NPSs by affecting these biomarkers. Results from this proposal will deepen the understanding of the neural substrate underlying NPSs of AD, and therefore, inspire novel treatments.